Thesis (Ph. D.)--University of Hong Kong, 1997. / Includes bibliographical references (leaves 145-155).

Thesis (Ph.D.)--Cleveland State University, 2009. / Abstract. Title from PDF t.p. (viewed on Sept. 28, 2009). Includes bibliographical references (p. 84-90). Available online via the OhioLINK ETD Center and also available in print.

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published_or_final_version / Zoology / Doctoral / Doctor of Philosophy

<p>Endozepine is an alternative name for the testis-specific isoform of the acyl-CoA binding protein (t-ACBP). Acyl-CoA binding proteins form a highly conserved family of proteins, which bind long chain fatty acid esters with nanomolar affinity. They are also known to be endogenous ligands to the --amino butyric acid (GABA) receptor in the central nervous system and to play a role in a wide variety of cellular functions such as vesicular trafficking, fatty acid biosynthesis and gene regulation. A role for endozepine in apoptosis was suggested through promoter gene trapping studies using CHO22 cells in which 90 % reduction in the expression of endozepine correlated with delayed mitochondrial permeabilization, a reduced activation of caspase-3 (an activator of apoptosis) and a consequent resistance to C2-ceramide induced apoptosis.</p> <p>Transduction studies using Tat-GFP-ELP fusion protein showed that endozepine restored the sensitivity of mutant CHO22 cells to C2-ceramide induced apoptosis. In this thesis, we have investigated two hypotheses for the involvement of endozepine in ceramide-induced apoptosis. The first hypothesis is that endozepine contributes to apoptosis through the transport of palmitoyl-CoA, a substrate required for the de novo synthesis of ceramide. The second hypothesis is that endozepine interacts directly with ceramide leading to interaction with peripheral benzodiazepine receptor and a subsequent opening of the mitochondria permeability transition pore, leading to apoptosis.</p>

Thesis advisor: Steven D. Bruner / Thesis advisor: Larry W. McLaughlin / Nonribosomal peptides are therapeutically important natural products produced through pathways that utilize large multimodular enzymes, termed nonribosomal peptide synthetases (NRPSs). Central to the assembly line methodology, the monomer building blocks and the growing polymer chain are covalently linked to dedicated peptidyl carrier protein domains as phosphopantetheinyl thioesters. Although structures of multidomain NRPS fragments have been solved recently, the active conformation of the carrier domains with their attached phosphopantetheinyl arms has not been determined. Significant conformational changes in carrier domains are likely to occur as the domains shuttle peptidyl phosphopantetheinyl thioesters between the active sites of the partner domains. This thesis focuses on the application of the synthetic isosteric non-hydrolyzable CoA analogs to manipulate carrier domain geometry of NRPS assemblies through. The synthetic conjugates are designed to deliver an inhibitor moiety to a domain of interest. Using this strategy, various complexes have been designed to direct the phosphopantetheinyl arm to active sites of adenylation domains and thioesterase domains in catalytically relevant conformations. The structurally restrained multidomain NRPS assemblies are useful for elucidating the complex structure and mechanism of NRPSs. An X-ray crystal structure of a peptidyl carrier-thioesterase NRPS didomain fragment from enterobactin synthetase has been solved with a phosphopantetheinyl analog which forms a cross-link between the two domains. This structure provides, for the first time, detailed insights into the phosphopantetheinyl arm interaction with an NRPS partner domain, as well as an active confirmation of a mutidomain NRPS in the holo-form. In addition, the hydrolytically stable CoA analogs have been successfully used as probes in the structural and mechanistic study of a CoA-utilizing enzyme DpgC, a unique cofactor-independent dioxygenase involved in vancomycin biosynthesis. / Thesis (PhD) — Boston College, 2009. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Diabetics often have elevated levels of serum lipids and cholesterol and increased risk of cardiovascular disease. Streptozotocin-induced diabetes was used to determine whether elevated serum cholesterol levels in diabetics are due to loss of control of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes the committed step in cholesterol synthesis. Strain A/ST female mice were fed 10% corn oil diets, half with 2% cholesterol. Experimental groups were injected with 9.0 mg streptozotocin / 100g body weight. Diabetes was confirmed by weight loss, elevated blood sugars, and enlarged spleens. Reductase activity was assayed spectrophotometrically. Serum cholesterol levels were determined by gas liquid chromatography. Both diabetic and control mice fed cholesterol had elevated serum cholesterol levels and decreased reductase activities. These observations suggest that HMG CoA reductase is not the primary control point in the control of serum cholesterol levels in diabetic mice. The increase in serum cholesterol in the SI mice was not more than in the control group, suggesting that increased serum cholesterol is not a key factor in the control of coronary heart disease and related diseases in diabetics. The HMG CoA reductase activity was reduced in both SI and control mice fed 2% cholesterol, but not significantly, possibly due to a small sample size. Other substances that control serum cholesterol are all density classes of lipoproteins (high, intermediate, low, and very low) as well as the chylomicrons. / Department of Biology

<p>Endozepine is an alternative name for the testis-specific isoform of the acyl-CoA binding protein (t-ACBP). Acyl-CoA binding proteins form a highly conserved family of proteins, which bind long chain fatty acid esters with nanomolar affinity. They are also known to be endogenous ligands to the --amino butyric acid (GABA) receptor in the central nervous system and to play a role in a wide variety of cellular functions such as vesicular trafficking, fatty acid biosynthesis and gene regulation. A role for endozepine in apoptosis was suggested through promoter gene trapping studies using CHO22 cells in which 90 % reduction in the expression of endozepine correlated with delayed mitochondrial permeabilization, a reduced activation of caspase-3 (an activator of apoptosis) and a consequent resistance to C2-ceramide induced apoptosis.</p> <p>Transduction studies using Tat-GFP-ELP fusion protein showed that endozepine restored the sensitivity of mutant CHO22 cells to C2-ceramide induced apoptosis. In this thesis, we have investigated two hypotheses for the involvement of endozepine in ceramide-induced apoptosis. The first hypothesis is that endozepine contributes to apoptosis through the transport of palmitoyl-CoA, a substrate required for the de novo synthesis of ceramide. The second hypothesis is that endozepine interacts directly with ceramide leading to interaction with peripheral benzodiazepine receptor and a subsequent opening of the mitochondria permeability transition pore, leading to apoptosis.</p>

Thesis (Ph. D.)--Auburn University. / Abstract. Vita. Includes bibliographical references (p. 162-173).